A new experimental therapy may help restore mitochondrial DNA in people with mitochondrial DNA depletion syndromes such as thymidine kinase 2 deficiency (TK2d), suggests early research presented recently at the Muscular Dystrophy Association Clinical and Scientific Conference.
Scientists reported that the drug candidate PX578 increased mitochondrial DNA levels and improved cellular energy function in laboratory models of these rare disorders, raising hope that the treatment could slow or stop disease progression.
Mitochondrial DNA depletion syndromes are severe inherited disorders in which cells lose large amounts of mitochondrial DNA, the genetic material that helps mitochondria produce energy. This loss disrupts oxidative phosphorylation, the process cells use to generate energy, and can lead to damage in multiple organs.
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Researchers are exploring PX578 as a potential treatment because it directly targets the biological process that drives mitochondrial DNA loss. The oral medication is designed to activate DNA polymerase gamma, also known as POLG, the enzyme responsible for copying mitochondrial DNA.
“Mutations in DNA polymerase γ (POLG), the sole polymerase for mtDNA [mitochondrial DNA] replication, are most prevalent, with over 300 variants identified,” the researchers explained. “These conditions result in profound morbidity and early mortality, and this genetic diversity underscores the urgent need for mutation-agnostic therapies.”
Because PX578 stimulates the enzyme itself rather than targeting a specific mutation, investigators believe it could help people with a wide range of genetic forms of disease, including TK2d.
Laboratory studies provided early evidence that the drug can restore mitochondrial DNA production. In patient-derived fibroblasts and neural stem cells carrying POLG mutations, PX578 stimulated mitochondrial DNA synthesis and increased mitochondrial DNA copy number. The treatment also improved mitochondrial function, suggesting cells were better able to generate energy.
Animal studies further supported these findings. In two mouse models of mitochondrial DNA depletion syndromes, researchers observed strong biological effects and favorable pharmacology, indicating the drug reached tissues and worked as intended. PX578 binds to an allosteric site where two subunits of the POLG enzyme interact, enhancing the enzyme’s activity and helping it replicate mitochondrial DNA more efficiently.
PX578 is now being tested in a phase 1 clinical trial involving healthy volunteers, and studies in patients with mitochondrial DNA depletion syndromes, including TK2d, are planned for 2026. If future trials confirm the early results, the therapy could represent a new type of treatment aimed at correcting the underlying cause of these diseases rather than only managing symptoms. For patients and families affected by TK2d, this approach could eventually offer a way to stabilize or potentially reverse the mitochondrial DNA loss that drives the condition.
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